The present invention relates to a series of new octahydronaphthalene oxime derivatives, which are derivatives of the known compounds designated as ML-236A, ML-236B, MB-530A and MB-530B. These compounds have the ability to inhibit the biosynthesis of cholesterol in vivo, and can therefore be used in the treatment and prophylaxis of hypercholesterolemia. The invention also provides processes for preparing these compounds and compositions and methods using them.
In recent years, a number of compounds having the essential skeletal structure of 3,5-dihydroxy-5-[2-(1-polyhydronaphthyl)ethyl]pentanoic acid have been discovered. The first of these, which were designated ML-236A and ML-236B, have the following formulae (i) and (ii), respectively: ##STR2## and are disclosed in U.S. Pat. No. 3,983,140. These compounds can exist either in the form of a lactone (shown in the formulae above) or as a corresponding free hydroxy-carboxylic acid. They have been isolated and purified from the metabolic products of microorganisms of the genus Penicillium, especially Penicillium citrinum, a species of blue mold. They have been shown to inhibit the biosynthesis of cholesterol by enzymes or cultured cells separated from experimental animals by competing with the rate-limiting enzyme active in the biosynthesis of cholesterol, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase and, as a result, significantly reduce serum chloresterol levels of animals [Journal of Antibiotics 29, 1346 (1976)].
Subsequently, another compound having a similar structure was discovered in the metabolic products of a mold of the genus Monascus, especially Monascus ruber, and this compound, which is disclosed inter alia in U.K. Patent Specification No. 2 046 737A may be represented by the formula (iii): ##STR3## This compound is referred to as "Monacolin K" in that United Kingdom Patent Specification, but has subsequently been referred to, and is herein referred to, as "MB-530B".
Subsequently, a similar compound, having similar antihypercholesteremic activity, was disclosed in U.K. Patent Specification No. 2 073 193A and was given the name "MB-530A"; this compound may be represented by the formula (iv): ##STR4##
Salts and esters of ML-236A, ML-236B, MB-530A and MB-530B are disclosed in U.K. Patent Specification No. 2 073 199, while further derivatives are disclosed in U.K. Patent Specification No. 2 075 013A.
The structure common to all of these compounds is shown below as formula (v), which also shows the numbering system employed herein to identify points of attachment and/or substitution; ##STR5##
All of the above-mentioned compounds have double bonds between the 4- and 10-positions and the 5- and 6-positions. The hypothetical compounds having the same structure except that the double bonds are between the 3- and 4-positions and the 10- and 5-positions are named by adding the prefix "iso" before the name of the parent compound. Thus, the "iso" compounds corresponding to the compounds of formulae (i) and may be represented by the following formulae (vi) to (ix), respectively: ##STR6##
As will be seen hereinafter, the nomenclature of the compounds of the present invention is based upon the names assigned to the compounds having the aforementioned formulae (i) to (iv) and (vi) to (ix).
We have now discovered a series of compounds which are derivatives of the ML-236 and MB-530 compounds; many of these new compounds have valuable antihypercholesteremic activity, the activities of some of these compounds being at least an order of magnitude greater than the activities of the known compounds.
Various derivatives of the primary compounds described above have been disclosed in the prior art. The prior art compounds believed to be closest structurally to the compounds of the present invention are disclosed in European Patent Publication No. 76 601, where there are disclosed ML-236A, ML-236B, MB-530A and MB-530B derivatives having a hydroxyimino group at the 4-position. These compounds differ from those of the present invention in the nature of the groups, at the 4- and/or 3-positions, and the compounds of the present invention have a substantially better cholesterol synthesis inhibitory activity than do these prior art compounds.